Multi-transgenic pig for Xenotransplantation
AssigneeRevivicor, Inc.
InventorsDavid L. Ayares, Carol Phelps
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Abstract
The present invention is directed to transgenic animals (e.g., transgenic porcine animals) comprising multiple genetic modifications that advantageously render these animals suitable donors for xenotransplanation. The present invention extends to organs, organ fragments, tissues and cells derived from these animals and their therapeutic use. The present invention further extends to methods of making such animals. In certain embodiments, the transgenic animals (e.g., transgenic porcine animals) lack expression of alpha gal and incorporate and express at least four transgenes under the control of at least two promoters.
Claims19
A transgenic pig comprising at least four transgenes, wherein:
- (i) the at least four transgenes are incorporated and expressed at a single locus under the control of at least two promoters;
- (ii) the single locus is a native or a modified locus selected from the group consisting of CMAH, β4GalNT2, and GGTA1, wherein the GGTA1 locus is a modified GGTA1 locus comprising a selectable marker gene or a large genomic insert;
- (iii) the transgenic pig lacks expression of alpha 1, 3 galactosyltransferase;
- (iv) two of the at least four transgenes are expressed as a first polycistron controlled by a first promoter and two of the four transgenes are expressed as a second polycistron controlled by a second promoter that is different from the first promoter;
- and
- the first polycistron comprises an endothelial cell-specific promoter driving the expression of TBM and CD47;
- and the second polycistron comprises a constitutive promoter driving the expression of EPCR and HO-1.
A transgenic alpha 1, 3 galactosyltransferase knockout pig comprising a human CD46 transgene and at least four transgenes incorporated and expressed at a single GGTAl locus under the control of a constitutive promoter and an endothelial cell specific promoter, or a constitutive promoter comprising an endothelium-specific enhancer element, wherein:
- (i) the single GGTA1 locus is a modified GGTAl locus comprising a selectable marker gene or a large genomic insert;
- (ii) two of the at least four transgenes are expressed as a first polycistron controlled by the endothelial cell-specific promoter and two of the four transgenes are expressed as a second polycistron controlled by the constitutive promoter ;
- and
- (iii) the first polycistron comprises TBM and CD47;
- and the second polycistron comprises EPCR and HO-1.
Dependencies are inferred from the claim text.